Regulatory T (Treg) cells, a specialized immune population, are known for their role in maintaining immunological tolerance. Mounting evidence has suggested that Treg cells not only come in ?different flavors? phenotypically and functionally but can play an even broader role in non-immune contexts such as cardiovascular disease, obesity-induced insulin resistance and tissue repair. In this proposed study, by taking advantage of an experimental system through which we could examine different tissue-specific Treg cell subsets simultaneously during the time when they are actively controlling ongoing autoimmune inflammation, we will identify key effector mechanisms underlying tissue-specific Treg cell-mediated immune regulation. In particular, our preliminary gene expression profiling study revealed that many genes involved in the MHC class II (MHCII) presenting pathway were specifically upregulated in Treg cells isolated from small intestine (SI Treg cells) under the inflammatory condition. To this end, by generating mice with conditional MHCII ablation in Treg cells, the function of MHCII pathway in gut-associated Treg cell-mediated intestinal homeostasis particularly during the presence of ongoing autoimmunity will be determined. Results obtained from this study will provide mechanistic insights into tissue specific-Treg cell-mediated immune regulation under different cellular and environmental settings. Ultimately, our study will further extend our fundamental knowledge of this functionally specialized Treg cell subset in regulating human health and disease.